The invention deals with functionalised polymers, containing structural unites derived from xcex1-amino acids and with the method of preparation thereof, providing the said polymers with a narrow distribution of molecular parameters and with well-defined functional groups.
Synthetic polymers of xcex1-amino acids, poly(AA), contain peptide bonds in the main chain and can be composed of the same structural units (xcex1-amino acids) as the poly(amino acid)s of natural origin, such as polypeptides and proteins. In this regard they may be considered as being protein analogues. In living systems, a combination of twenty amino acids provides for a vast number of structurally defined polymers, proteins, which fulfill essential functions in the living systems, thanks to their unique molecular structures. Uniqueness of molecular structure in proteins is a result of biosynthetic process of template polymerisation, leading to polymer product composed of molecules with identical composition and three-dimensional molecular structure.
Available methods for the synthesis of poly(AA) still remain far behind the specificity of the template-controlled polymerization in living systems and, usually, they provide heterogeneous mixtures of polymer molecules with statistical distributions of structural-units composition and polymer-chain lengths. The heterogeneity in the composition and molecular parameters constitutes the main difference between the synthetic poly(AA) and proteins. Similarly to other synthetics, the heterogeneity of the synthetic poly(AA) greatly limits their capability to form defined supramolecular structures and to be involved in molecularly specific interactions, typical for living systems. Therefore, great effort of modern macromolecular chemistry is concerned with the application of controlled polymerization processes to the synthesis of well-defined polymers with narrow distributions of molecular parameters, which would be suitable to form supramolecular structures with specific properties. One of the important approaches in this field is based on the synthesis of block copolymers which, in one molecule, combine polymer chains with different chemical and/or physical properties. Besides important technical applications of block copolymers for the modification of mechanical properties of polymer materials, well-defined block copolymers form spontaneously associated structures, organized molecular layers and supramolecular structures with novel properties. Because of these qualities, well-defined block copolymers attract increased attention of scientists and open new opportunities for commercial use.
Bloc copolymers of xcex1-amino acids, despite of their potential of being analogues of specific biopolymers, have not yet been used in a significant commercial application. The reason for that rests in the lack of suitable synthetic methods providing, in a practically convenient process, poly(AA) with a narrow distribution of molecular parameters and with functional end-groups suitable to make either a block copolymer or be used in other chemical modifications. Synthetic poly(AA) are usually prepared by ring-opening polymerisation of N-carboxyanhydrides (NCA) of respective xcex1-amino acids. There is a large amount of literature describing the synthesis of various poly(AA). A comprehensive review of known reactions leading to the polymerization of NCA and/or the reactions accompanying the polymerisation is provided in the book by Kricheldorf (Kricheldorf H. R. xcex1-Amino-acid-N-carboxyanhydrides and related heterocycles. Synthesis, properties and polymerisation. Springer Verlag, Berlin, 1987). These known procedures are based on two mechanisms of NCA polymerisation.
When so called amine mechanisms applies, the polymer chain propagates through a nucleophile group, usually amine, as the polymer chain end-group. This mechanism comes into effect when the polymerisation is initiated by a protic nucleophile, typically, a primary amine. The protic nucleophiles initiate the NCA polymerisation through the reaction with C-5 carbonyl of NCA ring. The opening of NCA ring provides carbamic acid which decarboxylates, yielding free amino-group as an end-group and carbon dioxide. Free amino group acts as a nucleophile, attacks another NCA molecules and in this way the polymer chain propagates. The properties of the resulting polymer product are dependent on the extent of side reactions. One of these reactions involves formation of a carbamate anion end group, which affects the reaction kinetics. Another side reaction, particularly important in polymerisation of esters of dicarboxylic amino acids, such as glutamates and aspartates, is the reaction of the nucleophile end-group with the side-chain ester in the last structural unit. This reaction leads to the loss of the terminal nucleophile group and, consequently, to the termination of the polymer chain. Due to side reactions, the resulting polymer product is heterogeneous, often with a bimodal molecular-weight distribution, and the structure polymer-chain end groups is uncertain.
Another mechanism of NCA polymerisation is the activated-monomer mechanism. This mechanism comes into effect when the polymerisation is initiated by a base, which cannot act as a nucleophile, e.g. a tertiary amine. Through the reaction of the base with the monomer (NCA), nitrogen in the NCA ring becomes deprotonated. The resulting NCA anion attacks another NCA molecule giving rise to a dimer containing a highly reactive N-acylated NCA group at one end, and a nucleophile carbamate group at the other. The chain propagation takes place through the reaction of another NCA anion (activated monomer) with the highly reactive N-acyl-NCA group. By perpetuation of this step the polymer chain growths rapidly, while the initiation of other polymer chains still proceeds through the much slower reaction of NCA anion with non-acylated monomer. Due to this kinetic course, a high-molecular-weight product is formed already at the early stages of monomer conversion and the resulting product has a wide molecular-weight distribution, and its final polymerisation degree is proportional neither to monomer conversion nor to a monomer-to-initiator ratio. The presence of another growing center, i.e. a nucleophile group at the other polymer chain, which allows for the propagation of the polymer by amine mechanism, represent another complicating factor. Consequently, the molecular parameters as well as the structure of the terminal functional groups cannot be controlled.
In spite of the numerous techniques described in the prior art, the prior art does not offer a method for obtaining poly(AA) with sufficiently low heterogeneity of molecular parameters and with defined functional end groups, which could be efficiently used in formation of biologically specific supramolecular assemblies and polymer materials.
We have found recently that the side reactions in the polymerisation of NCA can be significantly suppressed by using a initiating system, which prevents the formation of the second growing center and allows the polymer chain to growth predominantly, or exclusively, on prepared growing centers with known structure. In addition to that, we found that through the limitation of the propagation reaction to only one mechanism, the polymerisation conditions can be applied, at which it is possible to control the polymerisation degree of the growing polymer to obtain poly(AA) with desired polymerisation degree and narrow molecular-weight distribution. We also found, that while it is possible to select the structure of initiating system from a wide range of suitable amino-acid derivatives, it is also possible to select the structure of the initial, i.e. N-end terminal structural unit of poly(AA). Application of these new discoveries makes it possible to synthesize poly(AA) with desired narrow distribution of molecular parameters and with defined functional end groups, which are suitable for further chemical modification or for preparation of well-defined block copolymers. The functionalised polymers and block copolymers according to this invention can be used in various commercial applications as described above.
It is, therefore, the object of this invention to provide for polymers of xcex1-amino acids with narrow distribution of molecular weight and with defined functional groups at the polymer chain ends.
It is another object of this invention to provide a method for the synthesis of poly(amino acid)s with controlled molecular-weight distribution and for the controlling the average molecular weight of the final polymer product.
It is another object of this invention to provide a process for introduction of selected functional groups to the polymer chain ends and thus provide for homo-telechelic or hetero-telechelic polymers suitable for the synthesis of block copolymers containing poly(amino acid) segments